There is an urgent need to understand the biological and functional changes associated with brain aging, particularly when considering that age is the most potent risk factor for developing Alzheimer's disease (AD). Myelination and speed of mental processing both improve up to the mid-30's then breakdown or deteriorate progressively with advancing age. The similarity in trajectory between these two processes leads to the hypothesis that myelin breakdown may underlie the age-related slowing in cognitive speed. Apolipoprotein E4 (ApoE4) genotype increases the likelihood of developing AD and decreases age of onset. In healthy adults, presence of ApoE4 allele is associated with more rapid age-related cognitive deterioration while ApoE2 allele mitigates against cognitive decline. Cross-sectional data has demonstrated differential myelin breakdown in association with ApoE genotype with ApoE4 carriers manifesting more severe myelin breakdown. This proposal aims to investigate 1) the prospective change in myelin breakdown with age, 2) the relationship between prospective changes in myelin breakdown and processing speed, and 3) the effects of genetic markers on the prospective changes in biological and cognitive processes. We hypothesize that myelin will breakdown significantly with age; that myelin breakdown will be related to a decline in cognitive speed, and genetic status will modulate this structural-functional relationship. A cohort of 152 healthy elderly subjects underwent MRI and neuropsychological testing, producing some of the results summarized above. We plan to re-contact these subjects to repeat the imaging and cognitive testing using the same imaging protocol and test battery as the baseline evaluation. The inter-assessment interval will be about 6 years. This project will provide a rich source of longitudinal data that can be used to address questions beyond its major focus, such as predicting progression into clinically significant cognitive deficits (i.e., mild cognitive impairment; MCI). LAY LANGUAGE SUMMARY: By the time that a patient is diagnosed with MCI, they already have significant cognitive deficits and a substantial portion of such patients will develop Alzheimer's disease, which affects millions of people in the US and costs the healthcare system over $100 billion annually. This project has the potential to identify the interaction of imaging and genetic factors in predicting age-related cognitive decline leading to earlier implementation of clinical intervention or preventive efforts. [unreadable] [unreadable] [unreadable]